Signalling adaptor TRAF1 modulation, as a therapeutic target, to restore HCV-specific cytotoxic T cell response reactivity during chronic infection

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Larrubia, Juan-Ramón; Moreno-Cubero, Elia, 2017, "Signalling adaptor TRAF1 modulation, as a therapeutic target, to restore HCV-specific cytotoxic T cell response reactivity during chronic infection", https://doi.org/10.21950/P2RKZB, e-cienciaDatos, V2

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Description	Hepatitis C virus (HCV) worldwide infects around 170 million people. Two thirds of primo-infections develop a chronic disease that could lead to cirrhosis and hepatocellular carcinoma. This infection can be cured with direct acting anti-virals (DAA) but there are still difficult to treat cases relapsing after treatment, in which immunotherapy could play a role in curation. A successful immune response against HCV depends on virus-specific CD8+ T cells. During chronic infection, these cells are functionally impaired. The degree of this immune impairment could rely on the grade of co-stimulation failure over time of infection. The analysis of this dataset shows that: (1) Patients with short-mid lasting HCV infection had mild exhausted T cells, featured by loss of the key signal transducer (TRAF1) of the positive checkpoint 4-1BB/4-1BBL. (2) The functionality of these cells can be restored by IL-7-induced TRAF1 up-regulation, while in long-lasting infection to block the negative-costimulatory pathway PD-1/PD-L1 was also necessary. (3) Nevertheless, this last strategy was only useful in slow-fibrosers, suggesting an extreme T cell exhaustion or deletion in rapid fibrosers. In sum, our work supports novel ways of restoring specific CD8+ T cell response during chronic HCV infection, shedding light on the importance of TRAF1 signalling, which could be a promising target for immunotherapy in non-responders to DAA. (2017-05-03)
Subject	Medicine, Health and Life Sciences
Keyword	Infectious Diseases, Hepatology, Viral Hepatitis, CD8 T cell response, Exhaustion, Co-stimulation, Immunotherapy, Hepatitis C, 4-1BB, TRAF1, CD127, PD-1, Mcl-1
Related Publication	Moreno, E., Subirá, D., Sanz de Villalobos, E., Parra, T., Madejón, A., Miquel, J., … Larrubia, J. (2018). According to Hepatitis C Virus (HCV) Infection Stage, Interleukin-7 Plus 4-1BB Triggering Alone or Combined with PD-1 Blockade Increases TRAF1lowHCV-Specific CD8+Cell Reactivity. Journal of virology, 2018, v. 92, n. 2, p. 1-23 handle: http://hdl.handle.net/10017/32839
Notes	Research Institution: Guadalajara University Hospital. Health Service of Castilla-La Mancha. University of Alcalá, Spain. VER MAPA

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Citation Metadata

Dataset Persistent ID	doi:10.21950/P2RKZB
Publication Date	2017-05-03
Title	Signalling adaptor TRAF1 modulation, as a therapeutic target, to restore HCV-specific cytotoxic T cell response reactivity during chronic infection
Author	Larrubia, Juan-Ramón (Department of Medicine and Medical Specialties. University of Alcalá (UAH); Translational Hepatology Unit. Section of Digestive Diseases. Hospital Universitario de Guadalajara. Spain) - ORCID: http://orcid.org/0000-0002-6383-848X Moreno-Cubero, Elia (Department of Biology of Systems. University of Alcalá (UAH); Translational Hepatology Unit. Section of Digestive Diseases. Hospital Universitario de Guadalajara. Spain)
Contact	Use email button above to contact. Larrubia, Juan-Ramón (Department of Medicine and Medical Specialties. University of Alcalá (UAH))
Description	Hepatitis C virus (HCV) worldwide infects around 170 million people. Two thirds of primo-infections develop a chronic disease that could lead to cirrhosis and hepatocellular carcinoma. This infection can be cured with direct acting anti-virals (DAA) but there are still difficult to treat cases relapsing after treatment, in which immunotherapy could play a role in curation. A successful immune response against HCV depends on virus-specific CD8+ T cells. During chronic infection, these cells are functionally impaired. The degree of this immune impairment could rely on the grade of co-stimulation failure over time of infection. The analysis of this dataset shows that: (1) Patients with short-mid lasting HCV infection had mild exhausted T cells, featured by loss of the key signal transducer (TRAF1) of the positive checkpoint 4-1BB/4-1BBL. (2) The functionality of these cells can be restored by IL-7-induced TRAF1 up-regulation, while in long-lasting infection to block the negative-costimulatory pathway PD-1/PD-L1 was also necessary. (3) Nevertheless, this last strategy was only useful in slow-fibrosers, suggesting an extreme T cell exhaustion or deletion in rapid fibrosers. In sum, our work supports novel ways of restoring specific CD8+ T cell response during chronic HCV infection, shedding light on the importance of TRAF1 signalling, which could be a promising target for immunotherapy in non-responders to DAA. (2017-05-03)
Subject	Medicine, Health and Life Sciences
Keyword	Infectious Diseases Hepatology Viral Hepatitis CD8 T cell response Exhaustion Co-stimulation Immunotherapy Hepatitis C 4-1BB TRAF1 CD127 PD-1 Mcl-1
Related Publication	Moreno, E., Subirá, D., Sanz de Villalobos, E., Parra, T., Madejón, A., Miquel, J., … Larrubia, J. (2018). According to Hepatitis C Virus (HCV) Infection Stage, Interleukin-7 Plus 4-1BB Triggering Alone or Combined with PD-1 Blockade Increases TRAF1lowHCV-Specific CD8+Cell Reactivity. Journal of virology, 2018, v. 92, n. 2, p. 1-23 handle: http://hdl.handle.net/10017/32839 http://hdl.handle.net/10017/32839
Notes	Research Institution: Guadalajara University Hospital. Health Service of Castilla-La Mancha. University of Alcalá, Spain. VER MAPA
Language	English
Grant Information	Spanish Ministry of Economy and Competitiveness: PI12/00130 Carlos III Health Institute: PI15/00074
Depositor	Larrubia, Juan-Ramón
Deposit Date	2017-05-03

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Geographic Coverage	Spain, Madrid, Alcalá de Henares Spain, Guadalajara

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